Since its first rational development in 1957, 5-fluorouracil (5-FU) has been widely used as a chemotherapy reagent for various types of cancers, including colorectal, breast and pancreatic cancers (1). 5-FU is an antimetabolite that exerts its cytotoxic effect via several different mechanisms. These include reducing dTTP levels by inhibition of thymidylate synthase, misincorporation of both dUTP and FdUTP during DNA replication and repair of misincorporated dUTP and FdUTP, misincorporation of 5-FUTP into RNA and disruption of several aspects of RNA metabolism. Through its long history, the mechanism of action of 5-FU has been studied extensively, and a number of derivatives and combination therapies with other types of therapeutics have been developed to improve its effectiveness (2). Nevertheless these combination therapies often increase the risk of severe side effects limiting clinical application, and many tumor types exhibit a low response rate and/or rapidly acquire resistance (3).
5-Hydroxymethyl-2′-deoxyuridine (hmUdR) is a deoxyuridine analog, which can be formed by oxidation of thymine in cellular DNA exposed to ionizing radiation (4, 5). When added to culture medium, hmUdR is incorporated into cellular DNA, causing cytotoxicity in tumor cells (6-9). Interestingly, it has been reported that hmUdR synergistically enhances the growth inhibitory activity of 1-β-D-arabino5-FUranosylcytosine (Ara-C) by increasing the incorporation of the modified nucleoside into cellular DNA (10).
While examining the cytotoxicity of a number of base adducts generated by ionizing radiation, we found that a combination of 5-FU and hmUdR inhibited cell proliferation much more potently than either compound alone. We have demonstrated that hmUdR and other deoxyuridine analogs synergistically enhance the cytotoxicity of 5-FU in cancer but not normal cells by dramatically increasing the number of single strand breaks. See U.S. Pat. No. 8,617,540.
Extending our therapeutic and mechanistic understandings regarding cancer treatments using 5-FU and hmUdR to develop other synergistic 5-FU-based co-therapies would prove to be of great benefit to patients who suffer from cancers such as colorectal cancer (CRC).